Proapoptotic effect of endocannabinoids in prostate cancer cells

http://www.spandidos-publications.com/10.3892/or.2015.3746

• Authors:
  • O. Orellana-Serradell
  • C. E. Poblete
  • C. Sanchez
  • E. A. Castellón
  • I. Gallegos
  • C. Huidobro
  • M. N. Llanos
  • H. R. Contreras
• Corresponding author:
  • H. R. Contreras [ hcontrer@med.uchile.cl ]
• View Affiliations
  
• Published online on: Wednesday, January 21, 2015
• DOI: 10.3892/or.2015.3746

Abstract

In the early stages, prostate cancer is androgen‑ dependent; therefore, medical castration has shown significant results during the initial stages of this pathology. Despite this early effect, advanced prostate cancer is resilient to such treatment. Recent evidence shows that derivatives of Cannabis sativa and its analogs may exert a protective effect against different types of oncologic pathologies. The purpose of the present study was to detect the presence of cannabinoid receptors (CB1 and CB2) on cancer cells with a prostatic origin and to evaluate the effect of the in vitro use of synthetic analogs. In order to do this, we used a commercial cell line and primary cultures derived from prostate cancer and benign prostatic hyperplasia. The presence of the CB1 and CB2 receptors was determined by immunohistochemistry where we showed a higher expression of these receptors in later stages of the disease (samples with a high Gleason score). Later, treatments were conducted using anandamide, 2-arachidonoyl glycerol and a synthetic analog of anandamide, methanandamide. Using the MTT assay, we proved that the treatments produced a cell growth inhibitory effect on all the different prostate cancer cultures. This effect was demonstrated to be dose-dependent. The use of a specific CB1 receptor blocker (SR141716) confirmed that this effect was produced primarily from the activation of the CB1 receptor. In order to understand the MTT assay results, we determined cell cycle distribution by flow cytometry, which showed no variation at the different cell cycle stages in all the cultures after treatment. Treatment with endocannabinoids resulted in an increase in the percentage of apoptotic cells as determined by Annexin V assays and caused an increase in the levels of activated caspase-3 and a reduction in the levels of Bcl-2 confirming that the reduction in cell viability noted in the MTT assay was caused by the activation of the apoptotic pathway. Finally, we observed that endocannabinoid treatment activated the Erk pathway and at the same time, produced a decrease in the activation levels of the Akt pathway. Based on these results, we suggest that endocannabinoids may be a beneficial option for the treatment of prostate cancer that has become nonresponsive to common therapies.

 

see also...

Endocannabinoids in the Treatment of Prostate Cancer

German Scientists Have Confirmed an Amazing Link between Cannabis and Cancer Suppression

Researchers at the Institute of Toxicology and Pharmacology of Rostock University in Germany further confirm the profound benefits of Cannabis

 

R

esearchers at the Institute of Toxicology and Pharmacology of Rostock University in Germany rang in the New Year with excellent news for the world. In a study, Prof. Burkhard Hinz and his scientists put the active ingredients in cannabis up to the claims of holding an ability to truly kill cancer cells, even going further into the chemistry to find out exactly how this medical miracle takes place.  

Hinz’s repertoire with cannabis goes back a ways. In 2008 his research team was the first to discover that active ingredients actually slowed the migration of tumor cells into the surrounding tissues, this migration is what commonly leads metastasis, which is when cancer moves out from one affected area and into the rest of the body.   

The research has been published in the January 2015 edition of the journal Biochemical Pharmacology with the title “New Insights into Antimetastic and Antiangiogenic Effects of Cannabinoids.” What they found was that both tetrahydrocannabinol (THC or known as Delta-9-Tetrahydrocannabinol) and cannabidiol, also an active substance and originating from cannabis, contribute to the destruction of tumor cells by stimulating the formation of a specific protein, ICAM-1. By acting on the surface of the cells attacked by cancer, the proteins link themselves to the immune system’s own defensive cells, making the cancerous cells burst. The active ingredients, thus, prevent cancerous cells from forming blood vessels which allow the cancer to take root and grow.

This is, of course, very encouraging news, but the professor gave no timeline with respect to when his studies will progress onward with the process of producing an actual medicine. Hinz emphasized that the study is still at an early stage, and said, “We are far from putting our discoveries into practice on a clinical level. However, our results are further evidence that cannabinoids mediate a series of potentially therapeutic uses.” 

 

http://www.sciencedirect.com/science/article/pii/S1937644814000082

Chapter Two – New Insights into Antimetastatic and Antiangiogenic Effects of Cannabinoids

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Abstract

Cannabinoids exert antitumorigenic effects via multiple mechanisms. Of these, antimetastatic and antiangiogenic actions have attracted considerable interest in the past years. Regarding the underlying antimetastatic mechanism, several studies revealed cannabinoids to alter the gene expression of cancer cells toward a less-aggressive phenotype and to modulate their secretomic profile. Cannabinoids likewise modulate the release of factors from tumor cells that subsequently suppress the chemoattraction of vessel cells thereby conferring antiangiogenesis. Among the diverse mediators of cannabinoids' antitumorigenic action, the tissue inhibitor of matrix metalloproteinases-1, which is released from cancer cells upon cannabinoid treatment, has been implicated as a pivotal factor conferring both anti-invasive properties of cancer cells as well as antiangiogenic capacities of endothelial cells. In addition, cannabinoids have been shown to inhibit angiogenic capacities of endothelial cells directly via suppressing their proliferation, tube formation, and migration. This chapter reviews the cell- and substance-specific antitumorigenic mechanisms of cannabinoids with particular consideration of their antimetastatic/anti-invasive and antiangiogenic actions. In addition, beneficial interactions of cannabinoids with currently used chemotherapeutics as well as the influence of cannabinoids on tumor-immune surveillance are addressed. Collectively, the currently available data suggest cannabinoids as a potential tool in modern cancer pharmacotherapy.

Keywords

• Angiogenesis;
• Cancer;
• Cannabinoids;
• Metastasis;
• Tumor cell invasion

Corresponding author: E-mail: burkhard.hinz@med.uni-rostock.de

Study Shows THC May Limit Damage Caused By Heart Attack

http://www.medicaljane.com/2013/07/22/thc-is-beneficial-for-brain-heart-health/

Small Amounts Of THC Defend Against Heart Attacks

A recent study conducted by the Felsenstein Medical Research Center in Israel offered some new evidence of the medical value of Cannabis. The study, published in the Journal of Biochemical Pharmacology, was conducted to determine what effect small amounts of tetrahydrocannabinol (THC) has on heart protection. In order to do so, they conducted an experiment using mice as the subjects.

“A single ultra low dose of THC before ischemia [Insufficient Blood flow] is a safe and effective treatment that reduces myocardial ischemic [Heart Attack] damage.” – Felsenstein Medical Research Center, Israel

Researchers administered small amounts of THC (4 times less than the intoxicating amount) to mice before simulating a heart attack by restricting their blood flow.
The THC was administered on three different schedules in reference to the “heart attack”: 2 hours prior, 48 hours prior, and 3 weeks prior of continuous treatment.
In order to gauge the effect of THC in this study, researchers observed a number of common signs and/or residual effects of heart attacks. In each schedule of THC administration the study reported an improvement in each of the categories.

THC Has The Upper Hand On Cardiac Damage

Fractional Shortening is a ratio used to objectively rate the level of efficiency that a ventricle is working with. In observing this ratio, researchers found that THC treatment resulted in a 4.7% increase.
Troponin T is a regulatory protein found in cardiac muscle that leaks into the bloodstream in the case of cardiovascular damage. High volumes of it in the blood is often used to diagnose heart attacks. Researchers found that THC treatment reduced the amount of Troponin T by an average of 4 nano grams per milliliter.

The area of dead tissue caused by insufficient blood flow decreased by 6% after THC treatment.

In cases where blood is unable to reach a specific area, an infarction can form. This is an area in which the tissue dies, due to a process called necrosis. The researchers measured the size of these infarctions and found they decreased 6% after THC treatment.
Better heart health undoubtedly results in a longer lifespan. The study above suggests an ultra-low dose of THC can be beneficial in preparation for cardiac surgery. It could limit the damage incurred by the patient and possibly aid in the recovery.